The principal antitumor agents derived from the periwinkle plant, Vinca rosea Linn, are vinblastine and vincristine. These agents have been active in a variety of neoplastic disease including lymphomas, lymphocytic leukemia, and a variety of solid tumors. Due to the lack of myelosuppression with vincristine therapy, this agent has been included in numerous combination chemotherapy programs. However, neurotoxicity is a frequent side-effect and findings commonly include loss of reflexes, paresthesias, constipation, and muscle weakness. Discontinuation of the drug and reduction of the frequency of administration and/or dose are currently the only methods of altering these side-effects. The mechanism of the neurotoxicity may be linked to accumulation of the drug within neural tissues and disruption of microtubular function and repair (which cuases metaphase-arrest in dividing cells). Recently microtubular function has been restored in a rare disorder, Chediak-Higashi Disease, by the administration of agents which affect cyclic nucleotides. These nucleotides are important in the polymerization of microtubules from cytosol subunit proteins, tubulin. Therefore, the research plan would be to: 1) demonstrate the neurotoxic effects of repeated administration of vincristine in an animal model by observation of physical signs and ultrastructural changes in neural tissue; 2) administer agents which potentially could protect the development and function of microtubules in the neural tissues of the vincristine-treated animal and compare the physical signs and ultrastructural neural changes with those of the animals treated with vincristine only, and finally, 3) in the animal model bearing a potentially lethal burden of tumor cells, establish the most effective schedule of delivering VCR and the agents found to be antagonistic of vincristine-induced neurotoxicity in a fashion which will protect the neural system while preserving vincristine's antitumor effect. If methods can be developed to control vincristine-induced neurotoxicity, it is anticipated that greater patient comfort and more effective treatment with these agents will be possible. This research will be an integral part of the multidisciplinary Oncology Research Center at the Bowman Gray School of Medicine.